Nitro aliphatic compounds, process for preparation thereof and use thereof

ABSTRACT

New nitro aliphatic compounds and their pharmaceutically acceptable salts are disclosed.

This is a division of application Ser. No. 559,260, filed Dec. 8, 1983.

This invention relates to new nitro aliphatic compounds. Moreparticularly, this invention relates to new nitro aliphatic compoundsand their pharmaceutically acceptable salts, which have antithromboticand antihypertensive activity, to processes for preparation thereof, toa pharmaceutical composition comprising the same and to a method of usethereof.

New nitro aliphatic compounds of this invention are represented by thefollowing formula (I): ##STR1## wherein

R¹ is hydrogen, lower alkyl or lower alkoxy-phenyl,

R² is hydrogen or lower alkyl,

R³ and R⁵ are each hydrogen, or together to form a bond for getting agroup of the formula: ##STR2## wherein R⁴ and R⁶ are each as definedbelow,

R⁴ is lower alkyl,

R⁶ is hydrogen or lower alkyl,

R⁷ is hydrogen, hydroxyiminomethyl, cyano, formyl-piperazinecarbonyl,alkanoyl, esterified carboxy, lower alkyl which may have hydroxy orlower alkanoyloxy, or a group of the formula: ##STR3## wherein R⁸ and R⁹are each hydrogen, lower alkyl which may have one or more substituentsselected from carboxy, esterified carboxy, hydroxy and phenyl, or R⁸ andR⁹ are together to form piperidine ring, and R¹⁰ is hydrogen or loweralkyl which may have carboxy or esterified carboxy.

Particulars of the various definitions, which are mentioned hereinaboveand hereinafter, and preferred examples thereof are explained in thefollowing.

The term "lower" is intended to mean a group having 1 to 6 carbon atoms,unless otherwise provided.

(1) Re. Lower alkyl for R¹, R², R⁴, R⁶, R⁷, R_(a) ⁷, R⁸, R⁹, R¹⁰, R_(a)¹⁰, R_(b) ¹⁰ and R_(c) ¹⁰ :

Preferred examples of lower alkyl may include methyl, ethyl, propyl,butyl, pentyl, isopropyl, isobutyl, tert-butyl and the like.

(2) Re. Lower alkoxy moiety of lower alkoxyphenyl for R¹ :

Preferred examples of lower alkoxy may include methoxy, ethoxy, propoxy,butoxy, tert-butoxy and the like.

(3) Re. Alkanoyl for R⁷ and R_(a) ⁷ :

Preferred examples of alkanoyl may include formyl, acetyl, propionyl,butyryl, iso-butyryl, tert-butyryl, valeryl, pivaloyl, lauroyl, stearoyland the like.

(4) Re. Esterified carboxy for R⁷ and R_(a) ⁷, and esterified carboxymoiety for R⁸, R⁹, R¹⁰, R_(a) ¹⁰ and R_(b) ¹⁰ :

Preferred examples of esterified carboxy may include alkyl ester, i.ealkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, etc.) and the like.

(5) Re. Lower alkanoyloxy moiety for R⁷ and R_(a) ⁷ :

Preferred examples of lower alkanoyloxy may include acetoxy,propionyloxy, butyryloxy, tert-butyryloxy and the like.

A pharmaceutically acceptable salt of the compound (I) may include asalt with an inorganic or organic base such as an alkali metal salt(e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt(e.g. calcium salt, etc.), ammonium salt, an organic amine salts such asethanolamine salt, triethylamine salt, dicyclohexylamine salt and thelike.

The compound (I) and its pharmaceutically acceptable salts of thisinvention can be prepared by various methods, which are explained asfollows:

(1) Process 1: ##STR4##

(2) Process 2: ##STR5##

(3) Process 3: ##STR6##

(4) Process 4: ##STR7##

(5) Process 5: ##STR8##

(6) Process 6: ##STR9##

In the above formulae, R_(a) ⁷ is cyano, formyl-piperazinecarbonyl,alkanoyl, esterified carboxy, lower alkyl which may have hydroxy orlower alkanoyloxy, or a group of the formula: ##STR10## wherein R⁸ andR⁹ are each hydrogen, lower alkyl which may have one or moresubstituents selected from carboxy, esterified carboxy, hydroxy andphenyl, or R⁸ and R⁹ are together to form piperidine ring, R_(a) ¹⁰ islower alkyl which may have carboxy or esterified carboxy, R_(b) ¹⁰ islower alkyl having esterified carboxy, R_(c) ¹⁰ is lower alkyl havingcarboxy and R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each as defined above.

(1) Process 1: Compound (II)→Compound (I^(a))

The compound (I^(a)) and its salt can be prepared by reacting thecompound (II) or its salt with dinitrogen trioxide.

Preferred examples of salts of those compounds (II) and (I^(a)) mayinclude the same ones as those of the compound (I).

This reaction is carried out by reacting directly the compound (II) orits salt with dinitrogen trioxide. The dinitrogen trioxide is usuallyprepared by nitrous acid or its salt and an acid, and accordingly thisreaction is usually carried out by reacting the compound (II) or itssalt with nitrous acid or its salt in the presence of an acid, insteadthat such dinitrogen trioxide is directly employed.

Preferred examples of salts of nitrous acid may include an alkali metalsalt such as sodium salt, potassium salt and the like, an alkaline earthmetal salt such as calcium salt, and the like.

Preferred examples of acids may include an inorganic or organic acidsuch as hydrochloric acid, sulfuric acid, formic acid, acetic acid andthe like.

This reaction is preferably carried out in a solvent such as water,alcohol (e.g, methanol, ethanol, propanol, etc.), tetrahydrofuran,dioxane, dichloromethane or a mixture thereof.

This reaction is preferably carried out under somewhat milder conditionssuch as under cooling, at room temperature or under warming.

(2) Process 2: Compound (I^(b))→Compound (I^(c))

The compound (I^(c)) and its salt can be prepared by reacting thecompound (I^(b)) or its salt with an alkylating agent.

Preferred examples of salts of those compounds (I^(c)) and (I^(b)) mayinclude the same ones as those of the compound (I).

Preferred examples of an alkylating agent may include adiazo(lower)alkane (e.g. diazomethan, diazoethane, etc.), analkoxycarbonyl-alkylhalide (e.g., tert-butoxy carbonylmethyl bromide,methoxycarbonylmethylchloride, etc.), carboxy-alkylhalide (e.g.carboxymethylbromide, carboxy-methylchloride, etc.), and the like.

This reaction is preferably carried out in a solvent such as an alcohol(e.g. methanol, ethanol, etc.), N,N-dimethylformamide, water or amixture thereof.

This reaction is usually carried out under cooling or at roomtemperature.

(3) Process 3: Compound (I^(d))→Compound (I^(e))

The compound (I^(e)) and its salt can be prepared by subjecting thecompound (I^(d)) or its salt to de-esterification reaction.

Preferred examples of salts of those compounds (I^(e)) and (I^(d)) mayinclude the same ones as those of the compound (I).

The de-esterification reaction is carried out by a conventional methodsuch as hydrolysis, reduction or the like, details of which areexplained in the following:

(1) Hydrolysis:

Hydrolysis is preferably carried out in the presence of an acid or base.

Suitable acid includes an inorganic acid (e.g. hydrochloric acid,hydrobromic acid, sulfuric acid, etc.), an organic acid (e.g. formicacid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc.), and the like.

Suitable base includes an inorganic base such as alkali or alkalineearth metal hydroxide or the corresponding carbonate or bicarbonate(e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium bicarbonate, calcium hydroxide, etc.), ammoniumhydroxide or the like; an organic base such as an alkoxide or phenoxideof the above metal (e.g. sodium ethoxide, sodium methoxide, etc.), anamine such as mono-, di or tri-alkylamine (e.g. methylamine, ethylamine,N,N-dimethyl-1,3-propanediamine, trimethylamine, triethylamine, etc.) orthe like.

The hydrolysis is preferably conducted under somewhat milder conditionssuch as under cooling or under warming in a solvent which does not haveadverse influence to the reaction, e.g. water, a hydrophilic solventsuch as alcohol (e.g. methanol, ethanol, propanol, etc.), acetone,N,N-dimethylformamide, etc. A liquid abovementioned acid and base canalso be used as a solvent.

(2) Reduction:

Reduction, including chemical reduction and catalytic reduction, iscarried out in a conventional manner.

Suitable reducing agents to be used in chemical reduction are a metal(e.g. tin, zinc, iron, etc.), or a combination of such metal and/ormetallic compound (e.g. chromium chloride, chromium acetate, etc.) andan organic or inorganic acid (e.g. formic acid, acetic acid, propionicacid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g. platinum plate, spongy platinumplatinum black, colloidal platinum, platinum oxide, etc.), palladiumcatalysts (e.g. spongy palladium, palladium black, palladium oxide,palladium on carbon, colloidal palladium, etc.), or the like.

The reduction is usually carried out in a solvent such as water, analcohol (e.g. methanol, ethanol, etc.) or the like.

The reduction is preferably carried out under somewhat milder conditionssuch as under cooling, at room temperature or under warming.

(4) Process 4: Compound (I^(f))→Compound (I^(g))

The compound (I^(g)) and its salt can be prepared by reacting thecompound (I^(f)) or its salt with hydroxylamine or its acid additionsalt.

Preferred examples of salts of those compounds (I^(f)) and (I^(g)) mayinclude the same ones as those of the compound (I).

Preferred examples of acid addition salts of hydroxylamine may includeones with an organic or inorganic acid such as methane sulfonate,p-toluene sulfonate, hydrochloride, sulfate, nitrate, phosphate and thelike.

The reaction is usually carried out in a solvent such as an alcohol(e.g. methanol, ethanol, etc.), chloroform, tetrahydrofuran,dichloromethane or a mixture thereof.

This reaction is preferably carried out under somewhat milder conditionssuch as under cooling or at room temperature.

(5) Process 5: Compound (I^(f))→Compound (I^(h))

The compound (I^(h)) and its salt can be prepared by reducing thecompound (I^(f)) or its salt.

Preferred examples of salts of the compound (I^(h)) may include the sameones as those of the compound (I).

The reduction is carried out by a conventional method such as acatalytic reduction and a chemical reduction.

Preferred examples of catalysts to be used for a catalytic reduction mayinclude the same ones as those illustrated for the catalyst in theaforementioned Process 3.

Preferred examples of a reducing agent to be used for a chemicalreduction may include an alkali borohydride such as sodium borohydride,potassium borohydride and the like in addition to one illustrated forthe chemical reduction in the aforementioned Process 3.

The reaction conditions for the reduction (i.e. reaction solvent,reaction temperature, etc.) may optionally be selected in accordancewith the reduction method to be used. In general, it is preferable toemploy a solvent such as water, an alcohol (e.g. methanol, ethanol,etc.) or a mixture thereof.

The reaction is preferably carried out under somewhat milder conditionssuch as under cooling or at room temperature.

(6) Process 6: Compound (III)→Compound (Ii)

The compound (Ii) and its salts can be prepared by reacting the compound(III) or its salt with hydroxylamine or its salt.

Preferred examples of salts of the compound (Ii) may include the sameones as those of the compound (I).

This reaction is carried out in the substantially same manner as that ofthe aforementioned Process 4.

The starting compounds (II) and (III) to be used in this invention arethe new ones and some of them can be prepared by a method as follows andPreparations as described below, and the other compounds can be preparedby the substantially same methods as these methods. ##STR11##

In the above formulae, R¹, R², R⁴, R⁸ and R⁹ are each as defined above.

The compound (II^(a)) or its salt can be prepared by reacting thecompound (IV) or its salt with an amine compound of the formula:##STR12## (wherein R⁸ and R⁹ are each as defined above) or its salt.

Preferred examples of salt of the compound (II^(a)) may include the sameones as those of the compound (I).

Preferred examples of salts of the amine compound may include the sameones as those illustrated for the acid addition salt of hydroxylamine inthe aforementioned Process 4.

The reaction is preferably carried out as the first step by activatingthe carboxy group of the compound (IV) in a conventional manner, forexample, in a form of its activated ester, acid halide, acid anhydride,a mixed anhydride, etc., and then reacting the resulting compound withthe amine compound ##STR13## or its salt.

In case that the amine compound is used in the form of salt, thisreaction is preferably carried out in the presence of a base. Preferredexamples of such a base may include the same ones as those illustratedfor the base in the aforementioned Process 3.

This reaction is usually carried out in a solvent such astetrahydrofuran, dichloromethane, dioxane, water or a mixture thereof.

The reaction is preferably carried out under somewhat milder conditionssuch as under cooling or at room temperature.

As to the nitro-aliphatic compounds (I) and starting compounds (II) and(III), it is to be noted that each of said compounds includes one ormore stereo isomers and all of such isomers are included within thescope of this invention.

The new nitro aliphatic compounds (I) and their pharmaceuticallyacceptable salts of this invention have been found to possess relaxationeffect on smooth-muscles (e.g. cardiovascular dilating effect, etc.) andhypotensive effect, and further are capable of inhibiting plateletaggregation.

Accordingly, the new nitro aliphatic compounds (I) and theirpharmaceutically acceptable salts are useful for vasodilator which isused for the treatment of coronary insufficiency, angina pectoris andmyocardial infarction, and also useful for anti-hypertensive agent whichis used for the treatment of hypertension. Furthermore, they are used asan anti-thrombotic agent for the treatment of cerebral apoplexy,thrombosis and pulmonary embolism.

For the purpose of showing such pharmaceutical activities of the newnitro aliphatic compounds (I), pharmacological test data thereof areillustrated in the followings.

(i) Anti-platelet aggregation activity:

Inhibitory activity of the nitro aliphatic compounds of this inventionagainst rabbit platelet aggregation was measured according to the methoddescribed below.

Platelet aggregation:

Blood was collected from the central ear arteries of male Japanese Whiterabbit (2.5 to 3.0 kg body weight). The blood was prevented fromcoagulation with 1 volume of 3.8% sodium citrate to 9 volumes of blood.Platelet rich plasma (PRP) was prepared by centrifugation of the bloodat 1300 rpm for 10 min. at 10° C. The PRP was diluted with platelet poorplasma obtained by further centrifugation of the blood at 3000 rpm for10 min. The platelet counts in the PRP used for aggregation studies wereabout 4.0×10⁵ platelets/mm³. Aggregometry was performed with plateletaggregating agents in a SIENCO dual sample aggregometer (DP-274 E) at37° C., using 0.3 ml combined volume of PRP and reagents in acylindrical glass cuvette under constant stirring with a magneticstirring bar. Platelet aggregation was measured turbidimetrically byrecording changes in the light transmission of PRP during aggregation.Activities of inhibitors were expressed as IC₅₀ values i.e.concentrations required to inhibit the platelet aggregation responses by50%. Collagen was used in amounts (2 to 20 μg/ml for PRP) sufficient toinduce a response that was 80 to 90% of the maximum obtainable.Arachidonic acid was used at a final concentration of 5 μM. Similarly afinal concentration of adenosine di-phosphate (ADP), usually 1 to 5 μMwas choosen to induce approximately 75% of the maximum aggregation.Thrombin was used at a final concentration of 0.3 U/ml.

Results are shown in the following Tables 1 and 2.

                  TABLE 1                                                         ______________________________________                                                       IC.sub.50 value (μg/ml)                                                    Test Compound                                                  Inducers       (Example 1)                                                    ______________________________________                                        Collagen       0.07                                                           Thrombin       0.15                                                           ADP            0.15                                                           Arachidonic acid                                                                             0.75                                                           ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Test Compound  IC.sub.50 (μg/ml)                                           (Example Number)                                                                             (Inducer: Thrombin)                                            ______________________________________                                        Example 2      0.15                                                           Example 3      0.3                                                            Example 4      0.3                                                            Example 6      0.15                                                           Example 7      0.75                                                           Example 10     0.3                                                            Example 11     0.15                                                           Example 14     0.30                                                           Example 15     0.75                                                           Example 17     1.5                                                            Example 18     3.0                                                            Example 19     0.07                                                           Example 20     0.15                                                           Example 21     0.15                                                           Example 22     0.75                                                           Example 23     0.15                                                           Example 24     1.5                                                            Example 25     6.0                                                            Example 28     6.0                                                            ______________________________________                                    

(ii) Vasodilating activity in vitro:

The vasodilating activity of the nitro-aliphatic compound (I) wasmeasured by the superfusion technique. The method is as follows:

Male Sprague-Dawly rats of 8-10 weeks age were killed by a blow on thehead and the throracic aorta was quickly removed. After removing fattytissues, spiral strips (2 mm width and 50 mm length) were made from theaorta and were suspended under a resting tension of 1 gram in 30 mlorgan baths containing warm (37° C.) oxygenated (95% O₂ :5% CO₂) Tyrodesolution of the following composition: NaCl 137 mM (8 g/liter), KCl 2.7mM (0.2 g/liter), CaCl₂ 2H₂ O 1.8 mM (0.264 g/liter), MgCl₂ 6H₂ O 1.02mM (0.208 g/liter), NaHCO₃ 11.9 mM (1 g/liter), NaH₂ PO₄ 2H₂ O 0.42 mM(0.066 g/liter) and glucose 5.55 mM (1 g/liter).

The tissues were equilibrated for almost 90 minutes and then weresuperfused with Tyrode solution (10 ml/min) and noradrenaline-salinesolution (0.6 μg/ml) (0.5 ml/min.) which increases the tension of thetissues by about 500 mg. Changes of tension of the tissues were measuredisometrically by means of force displacement transducers coupled to apolygraph. The vasodilating activity is expressed as the dose of eachcompound producing fifty percent reduction of the tension of the tissues(ED₅₀).

Results are shown in the following Table 3.

                  TABLE 3                                                         ______________________________________                                        Test Compound   Relaxation of aorta                                           (Example Number)                                                                              ED.sub.50 (μg)                                             ______________________________________                                        Example 1       0.05                                                          Example 2       0.20                                                          Example 3       0.10                                                          Example 4       0.10                                                          Example 6       2.0                                                           Example 7       0.5                                                           Example 10      5                                                             Example 11      0.1                                                           Example 12      0.05                                                          Example 13      0.25                                                          Example 14      0.05                                                          Example 15      2.5                                                           Example 17      0.25                                                          Example 18      0.025                                                         Example 19      0.01                                                          Example 20      0.1                                                           Example 21      0.05                                                          Example 22      0.25                                                          Example 23      0.025                                                         Example 25      5                                                             Example 26      5                                                             Example 27      0.25                                                          Example 28      0.5                                                           ______________________________________                                    

(iii) Hypotensive activity in experimental animal:

A 8 weeks-old Sprague-Dowley strain rat was anesthetized with urethane(0.7 g/kg, i.p). Blood pressure was recorded from femoral artery using atransducer coupled to a Biophysiograph 180 system (made by Sanei SokukiCo., Ltd.). The femoral vein was cannulated to permit intravenousinjection of the test compound. The test compound was dissolved insaline and injected in a volume of 0.2 ml. The results are shown in thefollowing Table 4.

                  TABLE 4                                                         ______________________________________                                                     Hypotensive effect                                               Test Compound  Maximal decrease                                               (Example number)                                                                             (mm Hg)      Duration (min)                                    ______________________________________                                        Example 1                                                                             100 μg/kg                                                                             40           4                                                      10 μg/kg                                                                             10           1.5                                           ______________________________________                                    

The pharmaceutical composition of this invention can be used in the formof a pharmaceutical preparation, for example, in solid, semisolid orliquid form, which contains an active substance of this invention inadmixture with an organic or inorganic carrier or excipient suitable forexternal, enteral or parenteral applications. The active ingredient maybe compounded, for example, with the usual non-toxic, pharmaceuticallyacceptable carriers for tablets, pellets, capsules, suppositories,solutions, emulsions, suspensions, and any other form suitable for use.The carriers which can be used are water, glucose, lactose, gum acacia,gelatin, mannitol, starch paste, magnesium trisilicate, talc, cornstarch, keratin, colloidal silica, potato starch, urea and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form, and in addition auxiliary, stablilizing,thickening and coloring agents and perfumes may be used. Thepharmaceutical compositions can also contain preservative orbacteriostatic agents to keep the active ingredient in the desiredpreparations stable in activity. The active object compound is includedin the pharmaceutical composition in an amount sufficient to produce thedesired therapeutic effect upon the process or condition of diseases.

For applying this composition to humans, it is preferable to apply it byintravenous, intramuscular or oral administration. While the dosage ortherapeutically effective amount of the object compound of thisinvention varies from and also depends upon the age and condition ofeach individual patient to be treated, a daily dose of about 0.1-100 mgof the active ingredient/kg of a human being or an animal is generallygiven for treating diseases, and an average single dose of about 10 mg,50 mg, 100 mg, 250 mg, and 500 mg is generally administered.

The following examples are given for purpose of illustrating thisinvention.

PREPARATION 1

Triethyl phosphonacetate (448 g) was added dropwise to sodium hydride(88 g, 60%) in anhydrous benzene (2 l) at 0° C. with stirring under drynitrogen atomosphere. After the mixture was stirred at room temperaturefor 30 minutes, (E)-2-ethyl-2-butenal (196 g) was added thereto slowlyat 0° C. The resulting mixture was allowed to stand at room temperaturefor 30 minutes, diluted with water (2 l) and then extracted with twoportions of ethyl acetate (1 l×2). The combined extracts were washedsuccessively with water and brine, and then dried over magnesiumsulfate. Removal of the solvent gave an oil which was purified bydistillation under reduced pressure to give ethyl(E,E)-4-ethyl-2,4-hexadienoate (290 g).

NMR: δ (CDCl₃) 7.2 (1H, d, J=16 Hz), 6.07-5.67 (2H, m), 4.2 (2H, q, J=7Hz), 2.26 (2H, q, J=7 Hz), 1.78 (3H, d, J=7 Hz), 1.27 (3H, t, J=7 Hz),0.97 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 2960, 2930, 2870, 1690, 1620, 1470, 1450,1390, 1370, 1310, 1275, 1265, 1250, 1180, 1100, 1080, 1060, 1040, 980,940, 870, 820 cm⁻¹

PREPARATION 2

Ethyl (E,E)-4-ethyl-2,4-hexadienoate (134 g) was dissolved in methanol(200 ml) and 1N aqueous sodium hydroxide (880 ml) was added to thesolution. The resulting mixture was stirred at room temperature for 20hours under nitrogen atmosphere. After removal of methanol, the residualaqueous solution was washed with ether. The aqueous layer was acidifiedwith conc. hydrochloric acid and then extracted with three portions ofethyl acetate (500 ml×3). The combined extracts were washed with brine,dried over magnesium sulfate and then evaporated to dryness to give awhite powder which was crystallized from ether to give(E,E)-4-ethyl-2,4-hexadienoic acid (108 g).

mp: 79°-81° C.

NMR: δ (CDCl₃) 11.2 (1H, broad s), 7.33 (1H, d, J=16 Hz), 6.00 (1H, q,J=7 Hz), 5.80 (1H, d, J=16 Hz), 2.29 (2H, q, J=7 Hz), 1.83 (3H, d, J=7Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 2970, 2930, 2880, 2700, 2600, 1680, 1620,1470, 1460, 1420, 1380, 1310, 1290, 1270, 1200, 1130, 1080, 1060, 990,960, 940, 870, 820 cm⁻¹

PREPARATION 3

(E,E)-4-Ethyl-2,4-hexadienoic acid (108 g) was dissolved intetrahydrofuran (2 l) and triethylamine (108 ml) was added to thesolution. The mixture was stirred at room temperature for 30 minutes andthen ethyl chloroformate (74 ml) was added dropwise thereto at -20° C.with stirring. The resulting mixture was stirred at the same temperaturefor 60 minutes, and then dry ammonia gas was bubbled into the reactionmixture at -20° C. for until the mixture was saturated with ammonia. Themixture was stirred at the same temperature for 60 minutes and thenconcentrated. The resulting concentrate was diluted with water and thenextracted with two portions of ethyl acetate (500 ml×2). The combinedextracts were washed successively with an aqueous sodium carbonate andbrine, dried over magnesium sulfate and then evaporated to dryness togive a pale yellow oil (79 g). The oil was crystallized from ether togive (E,E)-4-ethyl-2,4-hexadienamide (34 g) as colorless crystals.

mp: 57°-58° C.

NMR: δ (CDCl₃) 7.13 (1H, d, J=16 Hz), 6.2-5.7 (4H, m), 2.27 (2H, q, J=7Hz), 1.78 (3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3500, 3430, 3350, 3200, 3020, 3000,2950, 2900, 1670, 1620, 1590, 1460, 1400, 1380, 1310, 1280, 1240-1220,1100, 1080, 1060, 990, 970, 860, 820 cm⁻¹

PREPARATION 4

(E,E)-4-Ethyl-2,4-hexadienoic acid (5 g) was dissolved intetrahydrofuran (300 ml) and triethylamine (5 ml) was added to thesolution. The mixture was stirred at room temperature for 30 minutes andthen ethyl chloroformate (3.4 ml) was added dropwise thereto at -20° C.with stirring. The resulting mixture was stirred at the same temperaturefor 60 minutes. n-Butylamine (3.6 ml) was added to the reaction mixtureat -20° C. The resulting mixture was stirred at the same temperature for60 minutes. The reaction mixture was concentrated and the concentratewas diluted with water, and then extracted with two portions of ethylacetate (100 ml×2). The combined extracts were washed with successivelyan aqueous sodium carbonate solution and brine, dried over magnesiumsulfate and then evaporated to dryness to give an oil (6.5 g) which wassubjected to column chromatography on silicagel, eluting with chloroformcontaining 2% methanol, to give(E,E)-N-n-butyl-4-ethyl-2,4-hexadienamide (5.8 g).

NMR: δ (CDCl₃) 7.05 (1H, d, J=16 Hz), 6.33 (1H, broad s), 5.75 (1H, q,J=7 Hz), 5.7 (1H, d, J=16 Hz), 3.4-3.1 (2H, m), 2.22 (2H, q, J=7 Hz),1.77 (3H, d, J=7 Hz), 1.7-1.2 (4H, m), 1.1-0.8 (6H, m)

IR: ν_(Max) ^(CHCl).sbsp.3 3450, 3300, 2960, 2930, 2870, 1660, 1610,1510, 1470, 1450, 1440, 1320, 1300, 1260, 1200, 980, 820 cm⁻¹

PREPARATION 5

(E,E)-N-Methyl-4-ethyl-2,4-hexadienamide (2 g) was prepared insubstantially the same manner as that of Preparation 4 from(E,E)-4-ethyl-2,4-hexadienoic acid (5 g) and methylamine (40% in water,11 ml).

NMR: δ (CDCl₃) 7.13 (1H, d, J=16 Hz), 7.0 (1H, m), 5.9 (1H, d, J=16 Hz),5.87 (1H, q, J=7 Hz), 2.85 (3H, d, J=5 Hz), 2.22 (2H, q, J=7 Hz), 1.75(3H, d, J=7 Hz), 0.95 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3440, 3270, 2950, 2900, 2850, 1640, 1600,1520, 1410, 1320, 1260, 1050, 980, 820 cm⁻¹

PREPARATION 6

1-Formyl-4-[(E,E)-4-ethyl-2,4-hexadienoyl]piperazine (6.8 g) wasprepared in substantially the same manner as that of Preparation 4 from(E,E)-4-ethyl-2,4-hexadienoic acid (5 g) and 1-piperazinecarbaldehyde(7.4 ml).

NMR: δ (CDCl₃) 8.08 (1H, s), 7.23 (1H, d, J=16 Hz), 6.17 (1H, d, J=16Hz), 5.92 (1H, q, J=7 Hz), 3.7-3.3 (8H, m), 2.28 (2H, q, J=7 Hz), 1.78(3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 2970, 2950, 2900, 2850, 1660, 1630, 1610,1590, 1450, 1420, 1390, 1290, 1270, 1260, 1230, 1000 cm⁻¹

PREPARATION 7

To a solution of (E,E)-4-ethyl-2,4-hexadienoic acid (2.8 g) andN-hydroxysuccinimide (2.3 g) in dioxane (20 ml) was addeddicyclohexylcarbodiimide (4.32 g). The mixture was stirred at ambienttemperature overnight and then filtered. The filtrate was concentratedto dryness under reduced pressure to give a residue which was dissolvedin tetrahydrofuran (100 ml). To the solution was added a solution ofglycine (4.5 g) and triethylamine (8.34 ml) in water (60 ml). Theresulting mixture was stirred at ambient temperature for 5 hours,acidified with 1N hydrochloric acid and then extracted with ethylacetate. The extract was washed with water, dried over magnesiumsulfate, and then concentrated to dryness under reduced pressure to givea crystalline residue. The residue was triturated with a mixture ofchloroform and hexane to give N-[(E,E)-4-ethyl-2,4-hexadienoyl]glycine(1.72 g).

IR (Nujol): 3300, 1720, 1640, 1580 cm⁻¹

PREPARATION 8

N-[(E,E)-4-Ethyl-2,4-hexadienoyl]piperidine (1.8 g) was prepared insubstantially the same manner as that of Preparation 7 from(E,E)-4-ethyl-2,4-hexadienoic acid (1.4 g) and piperidine (10 ml).

IR: ν_(Max) ^(CHCl).sbsp.3 3250, 1685, 1640, 1600 cm⁻¹

PREPARATION 9

To a solution of (E,E)-4-ethyl-2,4-hexadienoic acid (7 g) andN-hydroxysuccinimide (5.75 g) in dioxane (100 ml) was addeddicyclohexylcarbodiimide (10.8 g). The mixture was stirred at ambienttemperature overnight and then filtered. The filtrate was concentratedunder reduced pressure to give a residue which was recrystallized from amixture of ether and petroleum ether to giveN-[(E,E)-4-ethyl-2,4-hexadienoyloxy]succinimide (10.73 g).

NMR: δ (CDCl₃) 7.45 (1H, d, J=16 Hz), 6.1 (1H, q, J=7 Hz), 5.9 (1H, d,J=16 Hz), 2.8 (4H, s), 2.3 (2H, q, J=7 Hz), 1.83 (3H, d, J=7 Hz), 1.0(3H, t, J=7 Hz)

PREPARATION 10

To a solution of N-[(E,E)-4-ethyl-2,4-hexadienoyloxy]succinimide (1.19g) in a mixture of tetrahydrofuran (50 ml) and dimethylformamide (30 ml)was added a solution of L-threonine (2.38 g) and triethylamine (2.78 ml)in water (50 ml). The mixture was stirred at ambient temperature for 6hours and then acidified with 1N hydrochloric acid. The resultingmixture was extracted with ethyl acetate, washed with water and thendried over magnesium sulfate. The solvent was distilled off underreduced pressure to give N-[(E,E)-4-ethyl-2,4-hexadienoyl]-L-threonine(640 mg).

IR: ν_(Max) ^(CHCl).sbsp.3 3400, 3300, 2950, 2900, 1715, 1650, 1600,1500 cm⁻¹

PREPARATION 11

(E,E)-N-Benzyl-4-ethyl-2,4-hexadienamide (1 g) was prepared insubstantially the same manner as that of Preparation 10 fromN-[(E,E)-4-ethyl-2,4-hexadienoyloxy]succinimide (1.19 g) and benzylamine(1 ml).

IR: ν_(Max) ^(CHCl).sbsp.3 3400, 1650, 1605, 1500 cm⁻¹

PREPARATION 12

Methyl 2-[(E,E)-4-ethyl-2,4-hexadienoylamino]acetate (11.5 g) wasprepared in the substantially same manner as that of Preparation 4 from(E,E)-4-ethyl-2,4-hexadienoic acid (10 g) and glycine methyl ester (12.8g).

NMR: δ (CDCl₃) 7.2 (1H, d, J=16 Hz), 6.33 (1H, broad s), 5.9 (1H, q, J=7Hz), 5.87 (1H, d, J=16 Hz), 4.15 (2H, d, J=6 Hz), 3.77 (3H, s), 2.27(2H, q, J=7 Hz), 1.8 (3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3430, 3000, 1740, 1660, 1610, 1510, 1440,1380 cm⁻¹

PREPARATION 13

To a mixture of sodium hydride (60% in oil, 7.5 g) and dry benzene (200ml) was added dropwise diethyl cyanomethylphosphonate (30 g) withstirring at 0° C. under dry nitrogen atmosphere. After stirring for 60minutes at room temperature, a solution of (E)-2-ethyl-2-butenal (16.6g) in dry benzene was added thereto at 0° C. with stirring. Theresulting mixture was allowed to stand at room temperature for 60minutes and diluted with warm water and then extracted with ethylacetate. The extract was washed successively with water and brine, andthen dried over magnsium sulfate. Removal of the solvent gave an oilwhich was purified by distillation under reduced pressure to give(E,E)-4-ethyl-2,4-hexadienenitrile (8.4 g).

NMR: δ (CDCl₃) 6.97 (1H, d, J=16 Hz), 5.93 (1H, q, J=7 Hz), 5.27 (1H, d,J=16 Hz), 2.27 (2H, q, J=7 Hz), 1.83 (3H, d, J=7 Hz), 1.0 (3H, t, J=7Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3000, 2250, 1630, 1605, 1480, 1460, 1400,1380, 1230, 975 cm⁻¹

PREPARATION 14

To a suspension of lithium aluminum hydride (1.8 g) in dry ether (150ml) was added dropwise a solution of ethyl(E,E)-4-ethyl-2,4-hexadienoate (10 g) in dry ether (10 ml) at 0° C.

The mixture was stirred at room temperature for 30 minutes and smallamount of water was added thereto to decompose the excess lithiumaluminum hydride, and then filtered. The filtrate was diluted with ethylacetate, washed successively with water and brine, and then dried overmagnesium sulfate. Removal of the solvent under reduced pressure gave anoil.

The oil was dissolved in chloroform (200 ml) and manganese dioxide (60g) was added to the solution. The resulting mixture was stirred at roomtemperature for 24 hours and filtered. The filtrate was evaporated todryness in vacuo to give (E,E)-4-ethyl-2,4-hexadienal (4.2 g).

NMR: δ (CDCl₃) 9.53 (1H, d, J=7 Hz), 7.03 (1H, d, J=16 Hz), 6.3-5.9 (2H,m), 2.3 (2H, q, J=7 Hz), 1.83 (3H, d, J=7 Hz), 1.0 (3H, q, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 2980, 2730, 1670, 1625, 1140, 970 cm⁻¹

PREPARATION 15

To a suspension of lithium aluminum hydride (0.18 g) in dry ether (20ml) was added a solution of ethyl (E,E)-4-ethyl-2,4-hexadienoate (1 g)in ether (5 ml) at 0° C. The resulting mixture was stirred at roomtemperature for 15 minutes. Small amount of water was added to thereaction mixture. The resulting mixture was filtered and the filtratewas washed successively with water and brine. Removal of the solventgave an oil.

To the residue were added pyridine (1 ml) and acetic anhydride (0.5 ml),and the mixture was allowed to stand at room temperature overnight.

The reaction mixture was poured into a cold 1N hydrochloric acidsolution (50 ml) and extracted with ethyl acetate. The extract waswashed successively with 5% aqueous sodium bicarbonate solution andbrine, dried over magnesium sulfate, and then evaporated to dryness togive (E,E)-1-acetoxy-4-ethyl-2,4-hexadiene (0.48 g)

IR: ν_(Max) ^(CHCl).sbsp.3 2980, 1720, 1640, 1460, 1380, 1240 cm⁻¹

PREPARATION 16

To a solution of nitroethane (56 ml) and benzyltrimethylammoniumhydroxide (40% in methanol, 7 ml) in dioxane (80 ml) was added methyl(E)-2-pentenoate (20 g) at 70° C. with stirring. The resulting mixturewas stirred at 70° C. for 2 hours. After cooling, the reaction mixturewas acidified with 1N hydrochloric acid, diluted with water, and thenextracted with ether. The extract was washed successively with water andbrine, dried over magnesium sulfate and then evaporated to dryness togive methyl 3-ethyl-4-nitro pentanoate (30 g).

NMR: δ (CDCl₃) 4.8 (1H, m), 3.75 (3H, s), 2.6-2.4 (3H, m), 1.8-1.3 (5H,m), 1.0 (3H, m)

IR: ν_(Max) ^(CHCl).sbsp.3 2960, 1730, 1545, 1460, 1440, 1390, 1200,1180 cm⁻¹

PREPARATION 17

Diisobutyl aluminum hydride (25% in toluene, 39 ml) was added to asolution of methyl 3-ethyl-4-nitro pentanoate (8.5 g) in dry toluene(300 ml) at -70° C. with stirring under nitrogen atmosphere. Theresulting mixture was stirred at -70° C. for an hour and 2N hydrochloricacid (40 ml) was added to the reaction mixture. The mixture was dilutedwith ethyl acetate and filtered. The filtrate was washed successivelywith water and brine, dried over magnesium sulfate, and then evaporatedto dryness.

The resulting oil was dissolved in dichloromethane (100 ml) andpyridinium chlorochromate (14 g) was added to the solution. Theresulting mixture was stirred at room temperature for an hour anddiluted with 5 volumes of ether. The supernatant was obtained bydecantation from the mixture and passed through a column of magnesiumsilicate. The passed solution was evaporated to dryness in vacuo to give3-ethyl-4-nitropentanal (5 g).

NMR: δ (CDCl₃) 9.8 (1H, broad s), 4.9-4.5 (1H, m), 2.8-2.3 (3H, m),1.7-1.3 (5H, m), 0.95 (3H, m)

IR: ν_(Max) ^(CHCl).sbsp.3 2960, 2720, 1720, 1550, 1460, 1390, 1360 cm⁻¹

PREPARATION 18

To a suspension of sodium cyanide (4.5 g) and 3-ethyl-4-nitro-pentanal(7.5 g) in ether (50 ml) was added conc. hydrochloric acid (7.5 ml) at0° C. with stirring. The resulting mixture was stirred at 0° C. for anhour, diluted with ether, washed successively with water and brine,dried over magnesium sulfate, and then evaporated to dryness in vacuo togive 4-ethyl-2-hydroxy-5-nitro-hexanenitrile (8.1 g).

IR: ν_(Max) ^(CHCl).sbsp.3 3600, 3400, 2960, 2250, 1550, 1460, 1390 cm⁻¹

PREPARATION 19

A mixture of conc. hydrochloric acid (2.4 ml) and conc. sulfuric acid(0.38 ml) was added to a solution of4-ethyl-2-hydroxy-5-nitrohexanenitrile (1 g) in ether (2 ml) at 0° C.with stirring. The resulting mixture was allowed to stand at roomtemperature overnight, diluted with cold water, and then extracted withethyl acetate. The extract was washed with successively with water and5% aqueous sodium bicarbonate, dried over magnesium sulfate and thenevaporated to dryness in vacuo to give4-ethyl-2-hydroxy-5-nitrohexanamide (0.46 g).

NMR: δ (CDCl₃) 6.8 (1H, broad s), 6.3 (1H, broad s), 4.75 (1H, m),4.3-4.0 (2H, m), 2.4-2.1 (1H, m), 1.9-1.3 (7H, m), 0.95 (3H, m)

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3500, 3400, 3000, 1680, 1550, 1400,1100 cm⁻¹

PREPARATION 20

N-[(E,E)-4-Ethyl-2,4-hexadienoyl]-4-aminobutyric acid (1 g) was preparedin the substantially same manner as that of Preparation 10 fromN-[(E,E)-4-ethyl-2,4-hexadienoyloxy]succinimide (1.19 g) and4-aminobutyric acid (2 g).

NMR: δ (CDCl₃) 7.2 (1H, d, J=14 Hz), 6.3-5.7 (4H, m), 3.5 (2H, m),2.7-2.0 (6H, m), 1.8 (3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3400, 2800-2400, 1700, 1650, 1600, 1520 cm⁻¹

PREPARATION 21

Triethylphosphonoacetate (11.52 g) was added dropwise to a suspension ofsodium hydride (2.08 g, 60%) in benzene (80 ml) at 0° C. The mixture wasstirred at room temperature for an hour and 2-ethyl-3-methyl-2-butenal(4.8 g) was added slowly thereto at 0° C. The resulting mixture wasstirred at room temperature for 2 hours and then allowed to stand at thesame temperature overnight. The reaction mixture was poured into waterand extracted with ether. The extract was washed with water, dried overmagnesium sulfate, and then concentrated to dryness under reducedpressure to give ethyl (E)-4-ethyl-5-methylhexa-2,4-dienoate (7.6 g).

NMR: δ (CDCl₃) 7.8 (1H, d, J=16 Hz), 5.8 (1H, d, J=16 Hz), 4.25 (2H, q,J=7 Hz), 2.3 (2H, q, J=7 Hz), 1.95 (3H, s), 1.88 (3H, s), 1.3 (3H, t,J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(max) ^(CHCl) ₃.sbsp. 2950, 1700, 1620 cm⁻¹

PREPARATION 22

(E)-4-Ethyl-5-methyl-hexa-2,4-dienoic acid (2.5 g) was prepared in thesubstantially same manner as that of Preparation 2 from ethyl(E)-4-ethyl-5-methylhexa-2,4-dienoate (6 g).

NMR: δ (CDCl₃) 8.4 (1H, broad s), 7.9 (1H, d, J=16 Hz), 5.8 (1H, d, J=16Hz), 2.3 (2H, q, J=7 Hz), 1.95 (3H, s), 1.85 (3H, s), 1.0 (3H, t, J=7Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3000, 3200-2400, 1690, 1615 cm⁻¹

PREPARATION 23

(E)-4-Ethyl-5-methylhexa-2,4-dienamide (1.2 g) was prepared in thesubstantially same manner as that of Preparation 4 from(E)-4-ethyl-5-methyl-hexa-2,4-dienoic acid (2.34 g).

NMR: δ (CDCl₃) 7.7 (1H, d, J=16 Hz), 5.8 (1H, d, J=16 Hz), 5.7 (2H,broad s), 2.3 (2H, q, J=7 Hz), 1.9 (3H, s), 1.85 (3H, s), 1.0 (3H, t,J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3450, 3000, 1720, 1670, 1615, 1590 cm⁻¹

PREPARATION 24

To a suspension of sodium hydride (1.3 g, 60%) in anhydrous benzene (150ml) was added dropwise triethyl phosphonoacetate (6.72 g) at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for anhour and (E)-3-ethyl-3-penten-2-one (3.36 g) was added to the reactionmixture. The resulting mixture was stirred at 60° C. for 20 hours anddiluted with water and then extracted with ethyl acetate. The extractwas washed with brine and dried over magnesium sulfate. The solvent wasremoved under reduced pressure and the residue was chromatographed on asilica gel column and eluted with a mixture of hexane and chloroform(1:1).

The fractions containing the object compound were combined and thesolvent was evaporated to dryness to give ethyl(E,E)-4-ethyl-3-methyl-2,4-hexadienoate (3.3 g).

NMR: δ (CDCl₃) 5.88 (1H, q, J=7 Hz), 5.73 (1H, s), 4.27 (2H, q, J=7 Hz),2.37 (2H, q, J=7 Hz), 2.30 (3H, s), 1.76 (3H, d, J=7 Hz), 1.30 (3H, t,J=7 Hz), 0.97 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 2960, 2930, 2870, 1690, 1620 cm⁻¹

PREPARATION 25

(E,E)-4-Ethyl-3-methyl-2,4-hexadienoic acid (1.28 g) was prepared in thesubstantially same manner as that of Preparation 2 from ethyl(E,E)-4-ethyl-3-methyl-2,4-hexadienoate (1.82 g).

NMR: δ (CDCl₃) 9.70-8.70 (1H, broad s), 5.95 (1H, q, J=7 Hz), 5.90 (1H,s), 2.35 (2H, q, J=7 Hz), 2.30 (3H, s), 1.78 (3H, d, J=7 Hz), 1.06 (3H,t, J=7 Hz)

IR: ν_(Max) ^(Nujol) 3100, 2830, 2700, 2600, 2400, 1695, 1610 cm⁻¹

PREPARATION 26

(E,E)-4-Ethyl-3-methyl-2,4-hexadienamide (730 mg) was prepared in thesubstantially same manner as that of Preparation 4 from(E,E)-4-ethyl-3-methyl-2,4-hexadienoic acid (1.23 g) and 28% aqueousammonia (10 ml).

NMR: δ (CDCl₃) 5.83 (1H, q, J=7 Hz), 5.80 (1H, s), 5.30-4.40 (2H, broads), 2.32 (2H, q, J=7 Hz), 2.24 (3H, s), 1.74 (3H, d, J=7 Hz), 0.96 (3H,t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3560, 3450, 3200, 3005, 2950, 2900, 1670,1610, 1590 cm⁻¹

PREPARATION 27

(E,E)-4-Methyl-2,4-hexadienamide (1.2 g) was prepared in thesubstantially same manner as that of Preparation 4 from(E,E)-4-methyl-2,4-hexadienoic acid (2.5 g) and 28% aqueous ammonia (10ml).

NMR: δ (CDCl₃) 7.23 (1H, d, J=16 Hz), 5.93 (3H, m), 5.80 (1H, d, J=16Hz), 1.73 (3H, s), 1.78 (3H, d, J=6 Hz)

IR: ν_(max) ^(CHCl).sbsp.3 3550, 3430, 3000, 1670, 1620, 1590, 1380,1340, 1070 cm⁻¹

PREPARATION 28

(E)-4-Methyl-2,4-pentadienamide (1.2 g) was prepared in thesubstantially same manner as that of Preparation 4 from(E)-4-methyl-2,4-pentadienoic acid (2.3 g) and 28% aqueous ammonia (10ml).

NMR: δ (CDCl₃) 7.28 (1H, d, J=15 Hz), 5.90 (1H, d, J=15 Hz), 6.10 (2H,m), 5.30 (2H, s), 1.87 (3H, s)

IR: ν_(Max) ^(CHCl).sbsp.3 3500, 3420, 3350, 3200, 3000, 1675, 1630,1610, 1590, 1380, 1340, 1220 cm⁻¹

PREPARATION 29

Ethyl 2-((E)-4-methoxybenzylidene)butyrate (20 g) was prepared in thesubstantially same manner as that of Preparation 1 from ethyl2-diethylphosphonobutyrate (25 g) and p-methoxybenzaldehyde (12 g).

NMR: δ (CDCl₃) 7.57 (1H, s), 7.33 (2H, d, J=9 Hz), 6.88 (2H, d, J=9 Hz),4.27 (2H, q, J=7 Hz), 3.82 (3H, s), 2.58 (2H, q, J=7 Hz), 1.33 (3H, s),1.17 (3H, s)

IR: ν_(Max) ^(CHCl).sbsp.3 2960, 1695, 1605, 1240, 835 cm⁻¹

PREPARATION 30

To a suspension of lithium aluminum hydride (3 g) in dry ether (300 ml)was added a solution of ethyl 2-((E)-4-methoxybenzylidene)butyrate (19g) in dry ether (30 ml) at 0° C. with stirring. The mixture was stirredat the same temperature for 3 hours and excess lithium aluminum hydridewas decomposed with wet ether. The reaction mixture was filtered and thefiltrate was washed with water, dried over magnesium sulfate and thenevaporated to dryness to give 2-((E)-4-methoxybenzylidene)butan-1-ol (13g).

NMR: δ (CDCl₃) 7.23 (2H, d, J=8 Hz), 6.87 (2H, d, J=8 Hz), 6.45 (1H, s),4.23 (2H, s), 3.80 (3H, s), 2.37 (2H, q, J=7 Hz), 1.80 (1H, s), 1.10(3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3600, 3450, 2950, 1610, 1510, 1250, 830 cm⁻¹

PREPARATION 31

A mixture of 2-((E)-4-methoxybenzylidene)butan-1-ol (13 g) and manganesedioxide (130 g) in chloroform (600 ml) was stirred at room temperaturefor 20 hours. Manganese dioxide was filtered off by filtration and thefiltrate was condensed to give 2-((E)-4-methoxybenzylidene)butan-1-al(9.4 g).

NMR: δ (CDCl₃) 9.50 (1H, s), 7.90 (1H, s), 7.50 (2H, d, J=9 Hz), 6.97(2H, d, J=9 Hz), 3.83 (3H, s), 2.60 (2H, q, J=7 Hz), 1.13 (3H, t, J=7Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 2950, 1665, 1600, 1260, 1180, 830 cm⁻¹

PREPARATION 32

Ethyl (E)-4-((E)-4-methoxybenzylidene)-2-hexenate (9 g) was prepared inthe substantially same manner as that of Preparation 21 from2-((E)-4-methoxybenzylidene)-butan-1-al (9 g) and triethylphosphonoacetate (9.8 g).

NMR: δ (CDCl₃) 7.40 (1H, d, J=16 Hz), 7.33 (2H, d, J=8 Hz), 6.90 (2H, d,J=8 Hz), 6.73 (1H, s), 5.97 (1H, d, J=16 Hz), 4.27 (2H, q, J=7 Hz), 3.83(3H, s), 2.55 (2H, q, J=7 Hz), 1.33 (3H, t, J=7 Hz), 1.20 (3H, t, J=7Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 2960, 1695, 1600, 1260, 1175, 1035, 850 cm⁻¹

PREPARATION 33

(E)-4-((E)-4-Methoxybenzylidene)-2-hexenoic acid (3.1 g) was prepared inthe substantially same manner as that of Preparation 2 from ethyl(E)-4-((E)-4-methoxybenzylidene)-2-hexenate (3.7 g) and 1N sodiumhydroxide (20 ml).

NMR: δ (CDCl₃) 10.93 (1H, broad s), 7.53 (1H, d, J=16 Hz), 7.37 (2H, d,J=8 Hz), 6.93 (2H, d, J=8 Hz), 6.80 (1H, s), 6.00 (1H, d, J=16 Hz), 3.85(3H, s), 2.60 (2H, q, J=7 Hz), 1.23 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3400-2400, 1690, 1600, 1255, 1180, 860, 825cm⁻¹

PREPARATION 34

(E)-4-((E)-4-Methoxybenzylidene)-2-hexenamide (0.7 g) was prepared inthe substantially same manner as that of Preparation 4 from(E)-4-((E)-4-methoxybenzylidene)-2-hexenoic acid (1.25 g) and 28%aqueous ammonia (2 ml).

IR: ν_(Max) ^(CHCl).sbsp.3 3530, 3500, 3400, 3000, 2950, 1665, 1600,1585, 1255, 1180, 1030, 845 cm⁻¹

PREPARATION 35

(E,E)-N,N-dimethyl-4-ethyl-2,4-hexadienamide (1.7 g) was prepared in thesubstantially same manner as that of Preparation 4 from(E,E)-4-ethyl-2,4-hexadienoic acid (2 g) and dimethylamine hydrochloride(2.4 g).

NMR: δ (CDCl₃) 7.2 (1H, d, J=16 Hz), 6.2 (1H, d, J=16 Hz), 5.87 (1H, q,J=7 Hz), 3.03 (6H, s), 2.3 (2H, q, J=7 Hz), 1.77 (3H, d, J=7 Hz), 1.0(3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3000, 1680, 1640, 1600, 1400 cm⁻¹

Preparation 36

To a solution of 4-ethyl-2-hydroxy-5-nitrohexane nitrile (1.7 g) int-butanol (6.8 ml) was added conc. sulfuric acid (0.8 ml) at 0° C. withstirring. After stirring for an hour at room temperature, the mixturewas heated at 75° C. for an hour. The reaction mixture was diluted withwater and extracted with ethyl acetate. The extract was washedsuccessively with water and brine, dried over magnesium sulfate, andthen evaporated to dryness in vacuo. The resulting oil was dissolved inacetic acid (9 ml) and chromium trioxide (0.82 g) was added thereto. Theresulting mixture was heated at 100° C. for 1.5 hours with stirring,concentrated, diluted with water, and then extracted with ethyl acetate.The extract was washed successively with water and brine, and then driedover magnesium sulfate. Removal of the solvent gave an oil which waspurified by a preparative thin layer chromatography (solvent:chloroform)to give N-t-butyl-4-ethyl-5-nitro-2-oxo-hexanamide (0.46 g).

NMR: δ (CDCl₃) 6.8 (1H, broad s), 4.7 (1H, m), 3.0 (2H, d, J=6 Hz),2.7-2.5 (1H, m), 1.7-1.3 (14H, m), 0.9 (3H, m)

IR: ν_(Max) ^(CHCl).sbsp.3 3400, 2960, 1715, 1680, 1550, 1520, 1460,1390, 1370 cm⁻¹

PREPARATION 37

To a solution of 4-ethyl-2-hydroxy-5-nitrohexanamide (0.36 g) in aceticacid (5 ml) was added chromium trioxide (0.23 g). The resulting mixturewas heated at 100° C. for 40 minutes with stirring. After cooling, themixture was evaporated to dryness. The resulting residue was dilutedwith water and then extracted with ethyl acetate. The extract was washedsuccessively with water, an aqueous sodium bicarbonate and brine, andthen dried over magnesium sulfate. The solvent was removed bydistillation to give an oil. The oil was purified by a preparative thinlayer chromatography [solvent:methanol-chloroform (5:95)] to give4-ethyl-5-nitro-2-oxo-hexanamide (50 mg).

NMR: δ (CDCl₃) 6.8 (1H, broad s), 5.9 (1H, broad s), 4.7 (1H, m), 3.0(2H, d, J=6 Hz), 2.5 (1H, m), 1.7-1.2 (5H, m), 0.9 (3H, m)

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3420, 3000, 1710, 1555, 1400 cm⁻¹

PREPARATION 38

Sodium nitrite (0.6 g) was added to a (E,E)-4-ethyl-2,4-hexadienoic acid(0.3 g) in 20% aqueous dioxane (60 ml) with stirring. The mixture wasadjusted to pH 3.0. This operation was repeated more twice.

The resulting mixture was extracted with ethyl acetate (50 ml×2) and thecombined extracts were washed successively with water, 5% aqueousbicarbonate and brine, and then dried over magnesium sulfate. Removal ofthe solvent gave 3-ethyl-4-nitro-2-pentenal (0.2 g).

IR: ν_(Max) ^(CHCl).sbsp.3 2950, 2850, 2720, 1670, 1550, 1380 cm⁻¹

EXAMPLE 1

Sodium nitrite (60 g) was added to a (E,E)-4-ethyl-2,4-hexadienamide(31.4 g) in 10% aqueous methanol (1500 ml) with stirring, and themixture was adjusted to pH 3.0 and then stirred at room temperature for15 minutes. To the resulting reaction mixture was further added sodiumnitrite (60 g). The resulting mixture was adjusted to pH 3.0 and thenstirred at room temperature for 15 minutes. The resulting reactionmixture was extracted with ethyl acetate (500 ml×3) and the combinedextracts were washed with water and brine, respectively, dried overmagnesium sulfate and then evaporated to dryness to give a powder. Thepowder was washed with hot chloroform and then crystallized frommethanol to give (E)-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (20 g)as colorless prism.

mp: 142° C. (dec.)

NMR: δ (CD₃ OD) 6.17 (1H, s), 5.32 (1H, q, J=7 Hz), 2.15 (2H, q, J=7Hz), 1.72 (3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR (Nujol): 3500, 3300, 3070, 1660, 1600, 1560, 1390, 1310, 1290, 1200,1170, 1130, 1100, 1080, 1010, 960, 900, 870, 850, 800 cm⁻¹

EXAMPLE 2

Sodium nitrite (7 g) was added to a(E,E)-N-n-butyl-4-ethyl-2,4-hexadienamide (3 g) in 10% aqueous methanol(300 ml). The resulting mixture was adjusted to pH 3.0 and then stirredat room temperature for 15 minutes. To the resulting reaction mixturewas further added sodium nitrite (7 g), and the mixture was adjusted topH 3 and then stirred at room temperature for 15 minutes. This procedurewas repeated more three times. The resulting reaction mixture wasextracted twice with ethyl acetate (200 ml×2). The combined extractswere washed successively with water and brine, dried over magnesiumsulfate and then evaporated to dryness to give an oil. The oil wascolumn chromatographed on silica gel eluting with chloroform containing2% methanol to giveN-n-butyl-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (1.3 g).

NMR: δ (CD Cl₃) 6.8 (1H, broad s), 6.1 (1H, s), 5.15 (1H, q, J=7 Hz),3.5-3.2 (2H, m), 2.12 (2H, q, J=7 Hz), 1.72 (3H, d, J=7 Hz), 1.7-1.3(4H, m), 1.1-0.9 (6H, m)

IR: ν_(max) ^(CHCl).sbsp.3 : 3410, 3200, 2960, 2930, 2870, 1660, 1550,1530, 1460, 1380, 1360, 1000 cm⁻¹

EXAMPLE 3

N-Methyl-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (0.79 g) wasprepared in substantially the same manner as that of Example 2 from(E,E)-N-methyl-4-ethyl-2,4-hexadienamide (1.5 g) and sodium nitrite (12g).

NMR: δ (CDCl₃) 7.0 (1H, broad s), 6.13 (1H, s), 5.17 (1H, q, J=7 Hz),2.87 (3H, d, J=5 Hz), 2.12 (2H, q, J=7 Hz), 1.68 (3H, d, J=7 Hz), 0.97(3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3400, 3200, 2950, 2910, 2850, 1660, 1540,1450, 1410, 1380, 1340, 1030, 980 cm⁻¹

EXAMPLE 4

1-Formyl-4-(4-ethyl-2-hydroxyimino-5-nitro-3-hexenoyl)piperazine (0.6 g)was prepared in substantially the same manner as that of Example 2 from1-formyl-4-[(E,E)-4-ethyl-2,4-hexadienoyl]piperazine (1.4 g) and sodiumnitrite (12 g).

IR: ν_(Max) ^(CHCl).sbsp.3 3250, 3000, 2950, 2900, 1660, 1550, 1460,1440, 1400, 1360, 1280, 1240, 1200, 1180, 1000 cm⁻¹

EXAMPLE 5

To (E)-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (37 mg) in methanol(5 ml) was added excess etheral diazomethane at -20° C. The resultingmixture was allowed to stand at 0° C. for an hour and then acetic acidwas added thereto until the yellow color of the solution was discharged.The resulting reaction mixture was evaporated under reduced pressure togive an oil which was purified by preparative thin layer chromatography,developing with chloroform containing 5% methanol to give(E)-4-ethyl-2-methoxyimino-5-nitro-3-hexenamide (21.5 mg).

NMR: δ (CDCl₃) 6.56 (1H, m), 6.08 (1H, s), 5.5 (1H, m), 5.17 (1H, q, J=7Hz), 4.0 (3H, s), 2.12 (2H, q, J=7 Hz), 1.74 (3H, d, J=7 Hz), 1.02 (3H,t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3540, 3400, 3000, 1690, 1550, 1055 cm⁻¹

EXAMPLE 6

N-(4-Ethyl-2-hydroxyimino-5-nitro-3-hexenoyl)glycine (300 mg) wasprepared in the substantially same manner as that of Example 2 fromN-[(E,E)-4-ethyl-2,4-hexadienoyl]glycin (800 mg) and sodium nitrite (3g).

NMR: δ (CDCl₃ -CD₃ OD) 6.2 (1H, s), 5.25 (1H, q, J=7 Hz), 4.0 (2H, s),2.17 (2H, q, J=7 Hz), 1.75 (3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: IR: ν_(Max) ^(CHCl).sbsp.3 1720, 1670, 1550 cm⁻¹

EXAMPLE 7

N-(4-Ethyl-2-hydroxyimino-5-nitro-3-hexenoyl)piperidine (276 mg) wasprepared in the substantially same manner as that of Example 2 fromN-[(E,E)-4-ethyl-2,4-hexadienoyl]-piperidine (500 mg) and sodium nitrite(4 g).

NMR: δ (CDCl₃) 6.13 (1H, s), 5.15 (1H, q, J=7 Hz), 3.65 (4H, m), 2.27(2H, q, J=7 Hz), 1.75 (3H, d, J=7 Hz), 1.7 (6H, m), 1.05 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 1630, 1550, 1450 cm⁻¹

EXAMPLE 8

t-Butyl bromoacetate (200 μl) was added to a mixture of(E)-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (215 mg) and anhydrouspotassium carbonate (140 mg) in N,N-dimethylformamide (10 ml). Theresulting mixture was stirred at room temperature for an hour, pouredinto ice-water and then extracted with ethyl acetate. The extract waswashed with water, dried over magnesium sulfate and then concentrated todryness to give a residue (300 mg) which was purified by columnchromatography on silica gel to give2-t-butoxycarbonylmethoxyimino-4-ethyl-5-nitro-3-hexenamide (200 mg).

NMR: δ (CDCl₃ -CD₃ OD) 6.1 (1H, s), 5.4 (1H, m), 4.6 (2H, s), 2.2 (2H,m), 1.7 (3H, d, J=7 Hz), 1.5 (9H, s), 1.05 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3500, 3400, 2950, 2900, 1735, 1680, 1540,1450, 1365, 1220, 1150, 1090, 1020, 940, 920, 840 cm⁻¹

EXAMPLE 9

2-t-Butoxycarbonylmethoxyimino-4-ethyl-5-nitro-3-hexenamide (80 mg) wastreated with trifluoroacetic acid (1 ml) at ambient temperature for 2hours. Excess trifluoroacetic acid was distilled off under reducedpressure to give a residue which was purified by preparative thin layerchromatography, eluting with a mixture of benzene, dioxane and aceticacid (14:5:1) to give 2-carboxymethoxyimino-4-ethyl-5-nitro-3-hexenamide(32 mg).

NMR: δ (CD₃ OD) 6.2 (1H, s), 5.4 (1H, t, J=7 Hz), 4.7 (2H, s), 2.2 (2H,q, J=7 Hz), 1.7 (3H, d, J=7 Hz), 1.05 (3H, t, J=7 Hz)

EXAMPLE 10

N-(4-Ethyl-2-hydroxyimino-5-nitro-3-hexenoyl)-L-threonine (180 mg) wasprepared in the substantially same manner as that of Example 2 fromN-[(E,E)-4-ethyl-2,4-hexadienoyl]-L-threonine (600 mg) and sodiumnitrite (4 g).

NMR: δ (CDCl₃ -CD₃ OD) 6.2 (1H, s), 5.3 (1H, q, J=7 Hz), 4.8-4.0 (2H,m), 2.2 (2H, q, J=7 Hz), 1.7 (3H, d, J=7 Hz), 1.3 (3H, m), 1.0 (3H, d,J=7 Hz)

EXAMPLE 11

N-Benzyl-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (340 mg) wasprepared in the substantially same manner as that of Example 2 from(E,E)-N-benzyl-4-ethyl-2,4-hexadienamide (1 g) and sodium nitrite (4 g).

NMR: δ CDCl₃ -CD₃ OD) 7.3 (5H, s), 6.2 (1H, s), 5.2 (1H, q, J=7 Hz), 4.5(2H, d, J=5 Hz), 2.18 (2H, q, J=7 Hz), 1.8 (3H, d, J=7 Hz), 1.0 (3H, d,J=7 Hz)

EXAMPLE 12

2-Hydroxyimino-4-methyl-5-nitro-3-hexenamide (180 mg) was prepared inthe substantially same manner as that of Example 2 from(E,E)-4-methyl-2,4-hexadienamide (200 mg) and sodium nitrite (1500 mg).

NMR: δ (CD₃ OD) 6.22 (1H, s), 5.30 (1H, q, J=7 Hz), 1.68 (3H, s), 1.68(3H, d, J=7 Hz)

IR (Nujol): 3450, 3250, 2950, 1680, 1620, 1600, 1550, 1460, 1380, 1370,1000 cm⁻¹

EXAMPLE 13

2-Hydroxyimino-4-methyl-5-nitro-3-pentenamide (120 mg) was prepared inthe substantially same manner as that of Example 2 from(E)-4-methyl-2,4-pentadienamide (200 mg) and sodium nitrite (1500 mg).

NMR: δ (CD₃ OD) 6.23 (1H, s), 5.15 (2H, s), 2.07 (3H, s)

IR: ν_(Max) ^(CHCl).sbsp.3 3500, 3300, 2950, 1680, 1555, 1380 cm⁻¹

EXAMPLE 14

4-Ethyl-2-hydroxyimino-5-(4-methoxyphenyl)-5-nitro-3-pentenamide (210mg) was prepared in the substantially same manner as that of Example 2from (E)-4-((E)-4-methoxybenzylidene)-2-hexenamide (500 mg) and sodiumnitrite (3 g).

NMR: δ (CDCl₃) 7.40 (2H, d, J=8 Hz), 6.87 (2H, d, J=8 Hz), 6.86 (2H, m),6.23 (1H, s), 6.23 (1H, m), 5.90 (1H, s), 3.77 (3H, s), 2.03 (2H, q, J=7Hz), 0.97 (3H, t, J=7Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3420, 3000, 1695, 1620, 1560, 1365,1260, 1040

EXAMPLE 15

N-[4-Ethyl-2-hydroxyimino-5-nitro-3-hexenoyl]-4-aminobutyric acid (100mg) was prepared in the substantially same manner as that of Example 2from N-[(E,E)-4-ethyl-2,4-hexadienoyl]-4-aminobutyric acid (270 mg) andsodium nitrite (2 g).

NMR: δ (CDCl₃ -CD₃ OD) 6.2 (1H, s), 5.2 (1H, m), 3.5 (2H, m), 2.6-1.9(6H, m), 1.75 (3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

EXAMPLE 16

4-Ethyl-2-hydroxyimino-5-methyl-5-nitro-3-hexenamide (740 mg) wasprepared in the substantially same manner as that of Example 2 from(E)-4-ethyl-5-methyl-2,4-hexadienamide (1 g) and sodium nitrite (6 g).

NMR: δ (CDCl₃ -CD₃ OD) 6.2 (1H, s), 2.15 (2H, q, J=7 Hz), 1.8 (6H, s),0.95 (3H, t, J=7 Hz)

IR: ν_(Max) ^(Nujol) 3450, 1650, 1590, 1540 cm⁻¹

EXAMPLE 17

4-Ethyl-2-hydroxyimino-5-nitro-3-hexenenitrile (3.9 g) was prepared inthe substantially same manner as that of Example 2 from(E,E)-4-ethyl-2,4-hexadienenitrile (3 g) and sodium nitrite (12 g).

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3250, 3000, 2250, 1640, 1550, 1460,1390, 1360, 1040 cm⁻¹

EXAMPLE 18

4-Ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) was prepared in thesubstantially same manner as that of Example 2 from(E,E)-4-ethyl-2,4-hexadienal (0.3 g) and sodium nitrate (1.8 g).

NMR: δ (CDCl₃) 9.53 (1H, s), 6.03 (1H, s), 5.23 (1H, q, J=7 Hz), 2.15(2H, q, J=7 Hz), 1.77 (3H, d, J=7 Hz), 1.05 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3250, 3000, 1700, 1610, 1550, 1460,1390, 1360, 1040 cm⁻¹

EXAMPLE 19

Ethyl 4-ethyl-2-hydroxyimino-5-nitro-3-hexenoate (110 mg) was preparedin the substantially same manner as that of Example 2 from ethyl(E,E)-4-ethyl-2,4-hexadienoate (0.3 g) and sodium nitrite (1.8 g).

NMR: δ (CDCl₃) 10.3 (1H, broad s), 6.17 (1H, s), 5.23 (1H, q, J=7 Hz),4.3 (2H, q, J=7 Hz), 2.13 (2H, q, J=7 Hz), 1.73 (3H, d, J=7 Hz), 1.33(3H, t, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3570, 3250, 3000, 1725, 1555, 1390, 1030 cm⁻¹

EXAMPLE 20

Methyl 2-[4-ethyl-2-hydroxyimino-5-nitro-3-hexenoylamino]acetate (120mg) was prepared in the substantially same manner as that of Example 2from methyl 2-[(E,E)-4-ethyl-2,4-hexadienoylamino]acetate (0.3 g) andsodium nitrite (1.8 g).

NMR: δ (CDCl₃) 10.2 (1H, broad s), 7.42 (1H, broad s), 6.13 (1H, s), 5.2(1H, q, J=7 Hz), 4.12 (2H, d, J=6 Hz), 3.73 (3H, s), 2.12 (2H, q, J=7Hz), 1.7 (3H, d, J=7 Hz), 0.97 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3570, 3400, 3000, 1740, 1680, 1555, 1440,1390, 1230 cm⁻¹

EXAMPLE 21

Hydroxylamine hydrochloride (69.5 mg) was added to a solution of4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) in a mixture ofchloroform (3 ml) and methanol (2 ml) with stirring at room temperature.The resulting mixture was stirred at the same temperature overnight andevaporated to dryness. The residue was washed successively with water,aqueous sodium bicarbonate solution and brine, and dried over magnesiumsulfate. The solvent was distilled under reduced pressure to give aresidue which was purified by preparative thin layer chromatography[solvent:methanol-chloroform (10:90)] to give4-ethyl-2-hydroxyimino-5-nitro-3-hexenaldehyde oxime (65 mg).

NMR: δ (CDCl₃ -CD₃ OD) 7.77 (1H, s), 6.08 (1H, s), 5.23 (1H, q, J=7 Hz),2.15 (2H, q, J=7 Hz), 1.73 (3H, d, J=7 Hz), 1.0 (3H, t, J=7 Hz)

IR: ν_(Max) ^(Nujol) 3250, 2400, 1650, 1550, 960 cm⁻¹

EXAMPLE 22

To a solution of 4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) indry ethanol (10 ml) was added sodium borohydride (15 mg) at 0° C. withstirring. The resulting mixture was stirred at the same temperature for10 minutes and 1N hydrochloric acid was added thereto. The reactionmixture was extracted with ethyl acetate and the extract was washed withsuccessively with water, an aqueous sodium bicarbonate solution andbrine, dried over magnesium sulfate, and then evaporated to dryness invacuo to give an oil. The oil was purified by a preparative thin layerchromatography [solvent:methanol-chloroform (10:90)] to give4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-ol (80 mg).

NMR: δ (CDCl₃ -CD₃ OD) 6.17 (1H, s), 5.23 (1H, q, J=7 Hz), 4.23 (2H, s),2.23 (2H, q, J=7 Hz), 1.73 (3H, d, J=7 Hz), 1.05 (3H, t, J=7 Hz)

IR: ν_(Max) ^(CHCl).sbsp.3 3600, 3300, 3000, 1555, 1460, 1390, 1360 cm⁻¹

EXAMPLE 23

1-Acetoxy-4-ethyl-2-hydroxyimino-5-nitro-3-hexene (60 mg) was preparedin the substantially same manner as that of Example 2 from(E,E)-1-acetoxy-4-ethyl-2,4-hexadiene (0.3 g) and sodium nitrite (1.8g).

IR: ν_(Max) ^(CHCl).sbsp.3 3600, 3300, 3000, 1740, 1550, 1390, 1220 cm⁻¹

EXAMPLE 24

Hydroxylamine hydrochloride (60 mg) was added to a solution ofN-t-butyl-4-ethyl-5-nitro-2-oxo-hexanamide (100 mg) in a mixture ofchloroform (1.5 ml) and methanol (1 ml). The resulting mixture wasstirred at room temperature overnight.

The reaction mixture was evaporated and the resulting residue wasdiluted with ethyl acetate. The resulting solution was washedsuccessively with water and brine, dried over magnesium sulfate and thenevaporated to dryness. The resulting oil was purified by a preparativethin layer chromatography [solvent:benzene-ethyl acetate (10:1)] to giveN-t-butyl-4-ethyl-2-hydroxyimino-5-nitrohexanamide (47 mg).

NMR: δ (CDCl₃) 9.1 (1H, broad s), 6.7 (1H, broad s), 4.55 (1H, m),2.8-2.4 (3H, m), 1.7-1.2 (14H, m), 0.9 (3H, m)

IR: ν_(Max) ^(CHCl).sbsp.3 3600, 3410, 3300, 3000, 1670, 1630, 1550,1530, 1400, 1240, 1000 cm⁻¹

EXAMPLE 25

4-Ethyl-2-hydroxyimino-5-nitro-hexanamide (15 mg) was prepared in thesubstantially same manner as that of Example 24 from4-ethyl-5-nitro-2-oxo-hexanamide (20 mg) and hydroxylamine hydrochloride(14 mg).

NMR: δ (CDCl₃) 9.0 (1H, broad s), 6.7 (1H, broad s), 5.6 (1H, broad s),4.55 (1H, m), 2.8-2.4 (3H, m), 1.7-1.2 (5H, m), 0.9 (3H, m),

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3425, 3300, 3000, 1690, 1555, 1400,1000 cm⁻¹

EXAMPLE 26

4-Ethyl-2-hydroxyimino-3-methyl-5-nitro-3-hexenamide (170 mg) wasprepared in the substantially same manner as that of Example 2 from(E,E)-4-ethyl-3-methyl-2,4-hexadienamide (400 mg) and sodium nitrite(1600 mg).

NMR: δ (CD₃ OD) 5.68 (1H, q, J=7 Hz), 2.00 (2H, q, J=7 Hz), 1.92 (3H,s), 1.66 (3H, d, J=7 Hz), 0.90 (3H, t, J=7 Hz)

IR: ν_(Max) ^(Nujol) 3500, 3290, 3240, 3170, 1670, 1600, 1555 cm⁻¹

EXAMPLE 27

N,N-Dimethyl-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (203 mg) wasprepared in the substantially same manner as that of Example 2 from(E,E)-N,N-dimethyl-2,4-hexadienamide (0.3 g) and sodium nitrite (1.8 g).

IR: ν_(Max) ^(CHCl).sbsp.3 3570, 3250, 3000, 1640, 1550, 1380 cm⁻¹

EXAMPLE 28

Hydroxylamine hydrochloride (100 mg) was added to a solution of3-ethyl-4-nitro-2-pentenal (100 mg) in chloroform (3 ml) and methanol (2ml) with stirring. The resulting mixture was stirred at room temperatureovernight. The reaction mixture was evaporated to dryness and theresidue was diluted with water and extracted with ethyl acetate (50ml×2).

The combined extracts were washed successively with water, 5% sodiumbicarbonate and brine, and then dried over magnesium sulfate. Removal ofthe solvent gave an oil which was purified by a preparative thin layerchromatography (5% methanol-chloroform) to give3-ethyl-4-nitro-2-pentenal oxime (80 mg).

IR: ν_(Max) ^(CHCl).sbsp.3 3550, 3250, 2950, 1550, 1380 cm⁻¹

We claim:
 1. A compound of the formula or its pharmaceuticallyacceptable salt: ##STR14## wherein R¹ is hydrogen, lower alkyl, or loweralkoxy-phenyl,R² is hydrogen or lower alkyl, R⁴ is lower alkyl, R⁶ ishydrogen or lower alkyl, R⁷ is a group of the formula: ##STR15## whereinR⁸ and R⁹ are each hydrogen, lower alkyl which may have one or moresubstituents selected from carboxy, esterified carboxy, hydroxy andphenyl, or R⁸ and R⁹ together form a piperidine ring, and R¹⁰ ishydrogen or lower alkyl which may have carboxy or esterified carboxy. 2.A compound according to claim 1, wherein R⁷ is carbamoyl, R¹⁰ ishydrogen and R¹, R², R⁴ and R⁶ are each as defined in claim
 1. 3. Acompound according to claim 1, wherein R¹ is lower alkyl, R² ishydrogen, R⁴ is lower alkyl, R⁶ is hydrogen, R⁷ is carbamoyl, and R¹⁰ ishydrogen.
 4. A compound according to claim 1, wherein R¹ is methyl, R²is hydrogen, R⁴ is ethyl, R⁶ is hydrogen, R⁷ is carbamoyl and R¹⁰ ishydrogen.
 5. A pharmaceutical antithrombotic and antihypertensivecomposition comprising an effective amount of a compound as defined inclaim 1 or its pharmaceutical acceptable salt in association with apharmaceutically acceptable carrier or excipient.
 6. A method oftreating coronary insufficiency which comprises administering to asubject in need of such treatment an effective amount of the compound ofclaim
 1. 7. A method of treating angina pectoris, which comprisesadministering to a subject in need of such treatment an effective amountof the compound of claim
 1. 8. A method of treating myocardialinfarction which comprises administering to a subject in need of suchtreatment an effective amount of the compound of claim
 1. 9. A method oftreating hypertension which comprises administering to a subject in needof such treatment an effective amount of the compound of claim
 1. 10. Amethod of treating cerebral apoplexy which comprises administering to asubject in need of such treatment an effective amount of the compound ofclaim
 1. 11. A method of treating thrombosis which comprisesadministering to a subject in need of such treatment an effective amountof the compound of claim
 1. 12. A method of treating pulmonary embolismwhich comprises administering to a subject in need of such treatment aneffective amount of the compound of claim 1.